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Biomedical subjects

M M Khan

Publications and source records attributed to M M Khan.

At least 37 records · Page 2Linked to original sources
PubMed2001

Role of PML and PML-RARalpha in Mad-mediated transcriptional repression.

Fusion of the promyelocytic leukemia (PML) protein to the retinoic acid receptor-alpha (RARalpha) generates the transforming protein of acute promyelocytic leukemias. PML appears to be involved in multiple functions, including apoptosis and transcriptional activation by RAR, whereas PML-RARalpha blocks these functions of PML. However, the mechanisms of leukemogenesis by PML-RARalpha remain elusive. Here we show that PML interacts with multiple corepressors (c-Ski, N-CoR, and mSin3A) and histone deacetylase 1, and that this interaction is required for transcriptional repression mediated by the tumor suppressor Mad. PML-RARalpha has the two corepressor-interacting sites and inhibits Mad-mediated repression, suggesting that aberrant binding of PML-RARalpha to the corepressor complexes may lead to abrogation of the corepressor function. These mechanisms may contribute to events leading to leukemogenesis.

Animals↗
PubMed2001

The effects of histamine on interferon gamma production are dependent on the stimulatory signals.

Histamine regulates the immune response by enhancing TH2 cytokine production and by inhibiting TH1 cytokine production. We assessed the mechanisms of histamine's action on helper T cell subsets by evaluating the role of protein kinase A (PKA) in the histamine-mediated effects on IFN gamma production. The splenocytes and TH1 murine cloned cells (pGL10) were pretreated with histamine at a concentration range of 10(-8)-10(-5) M for 1 h and then were activated with anti-CD3, PHA, PMA + ionomycin, or ionomycin for 24 h. The levels of IFN gamma were measured in the supernatants by ELISA. The inhibitory effects of histamine were the most prominent in anti-CD3-stimulated splenocytes (61%). The effects of histamine on IFN gamma production from TH1 cells depended on the mode of cell activation. The activation of cells with anti-CD3 resulted in 27% inhibition of IFN gamma production whereas the activation with ionomycin produced 70% suppression. The inhibitory effects of histamine were completely reversed by cimetidine in a dose-dependent manner in both TH1 cells and in splenocytes. PKA played a role in the inhibition of IFN gamma by histamine when the cells were activated via TCR, and the PKA inhibitors Rp-cAMPS (10(-5) M) and H8 (10(-5) M) reversed the inhibitory effects of histamine on IFN gamma production. However, when the cells were stimulated with ionomycin, the PKA inhibitors did not affect histamine-mediated suppression of IFN gamma production.

Animals↗
PubMed2001

Histamine utilizes JAK-STAT pathway in regulating cytokine production.

Histamine shifts TH1/TH2 cytokine balance from TH1 to TH2 cytokines. The phosphorylation of STAT factors and their translocation to nucleus are important steps in the regulation of TH1/TH2 cytokine balance. This study was designed to investigate the effects of histamine on Janus kinases-signal transducers and activators of transcription (JAK-STAT) pathway. The splenocytes were treated with histamine in the presence or absence of JAK-STAT inhibitor, tyrphostin, activated with IFNgamma for 30 min, and phosphorylated STAT1 was detected by immunoblotting. We found that histamine up-regulated the phosphorylation of STATI and tyrphostin prevented this phosphorylation. We then studied the effects of tyrphostin on histamine-mediated inhibition of IFNgamma production and histamine-mediated stimulation of IL-5 and IL-10 production. Tyrphostin dose-dependently reversed the effects of histamine on IFNgamma, IL-5 and IL-10 production, as evident by ELISA. These observations suggest that histamine regulated JAK-STAT signal transduction, which is involved in cytokine secretion.

Animals↗
PubMed2001

Regulation of IL-13 production by histamine in cloned murine T helper type 2 cells.

Histamine affects the balance of T helper type 1 (Th1) and T helper type 2 (Th2) cytokines by shifting cytokine production from a Th1 to a Th2 pattern. Interleukin-13 (IL-13) is an important autacoid mediator that has been implicated in the development of allergic disease. This study was designed to investigate the mechanisms of regulation of IL-13 by histamine in Th2 cells. D10.G4.1 cells, a murine Th2 cell line, were treated with histamine (10(-8)-10(-4) M) and then activated with PMA (phorbol 12 myristate 13-acetate) plus ionomycin or alphaCD3. Levels of IL-13 production were then measured by enzyme-linked immunosorbent assay (ELISA) and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Cells were pretreated with histamine receptor antagonists pyrilamine, ranitidine, cimetidine and thioperamide to determine the involvement of histamine receptors. Cells were also pretreated with protein kinase A (PKA) inhibitors N-[2-(methylaminoethyl)]-5-isoquinoline-sulfonamide (H-8) and Rp-diastereomer of adenosine cyclic 3'5'-phosphorothionate (Rp-cAMPS), and Janus kinase-signal transducer and activator of transcription (Jak-STAT) inhibitor tyrphostin AG490 prior to the addition of histamine. H-8 is an inhibitor of the catalytic subunit of PKA while Rp-cAMPS is an inhibitor of the regulatory subunit of PKA. Tyrphostin is an inhibitor of Jak2, Jak3, STATI, STAT3 and STAT5. Finally, cells were pretreated with IL-12, a monokine known to repress STAT6 DNA binding. We found that histamine dose-dependently enhanced IL-13 secretion and mRNA levels in Th2 cells via H1 and H2 receptors. Pretreatment of cells with H-8, Rp-cAMPS and tyrphostin prevented histamine-induced secretion and transcription of IL-13. Likewise, pretreatment of Th2 cells with IL-12 also reversed histamine's effects on IL-13 secretion from stimulatory to inhibitory. These observations suggest a role for PKA and the Jak-STAT pathway in histamine-mediated elevation of IL-13 secretion and transcription.

Animals↗
PubMed2001

A cost-minimization approach to planning the geographical distribution of health facilities.

This paper illustrates a method of planning the geographic distribution of health facilities in order to maximize the social benefits achievable from the investment. Data from Bangladesh have been used to determine the optimal distribution of emergency obstetric care (EOC) facilities in the country using the estimates of average social cost per woman. Costs incurred by households, including the costs associated with maternal mortality, tend to increase with increasing radius of a facility's catchment area. The average facility-based costs tend to decline with increasing radius due to lower per capita capital expenditures. The summation of these two average cost functions generates a U-shaped curve. In this research, the minimum point of the aggregated average cost curve defines the 'optimal' radius of a health facility. The catchment area defined by the optimal radius minimizes the average social cost of providing EOC services in a region. The empirical analysis suggests that the optimal radius for the 20 regions of Bangladesh varies from about 6 to 12 km. If the optimal radius of the catchment area is used in planning health centre locations, Bangladesh will need to set up 450 EOC facilities; currently there are only 90 such facilities.

Bangladesh↗
PubMed2001

The second EF-hand is responsible for the isoform-specific sorting of myosin essential light chain.

It has been known that isoforms of myosin essential light chain (LC) exhibit the isoform-specific sorting within cardiac myocytes and fibroblasts. In order to analyze which domain of LC is responsible for the sorting, various chimeric cDNA constructs between human nonmuscle isoform (LC3nm) and chicken fast skeletal muscle isoform (LC3f) were generated and expressed in cultured chicken cardiac myocytes. If chimeras contained LC3f sequence at the place that was restricted by BssHII and PstI, they were preferentially sorted to sarcomeres and precisely localized at A-bands, and their incorporation levels into the A-bands were identical with that of the wild type LC3f. However, other chimeras were distributed throughout the cytoplasm like the wild type LC3nm. Comparison of amino acid sequences revealed that 12 amino acids are different between chicken LC3f and human LC3nm in the BssHII-PstI fragment, and these amino acids are located within the second EF-hand of LC. These results indicated that the second EF-hand is responsible for the isoform-specific sorting of LC. Although the second EF-hand is not included in the key contacts with myosin heavy chain, it is supposed that this domain is important for the relative disposition of neighboring domains. Thus, the 12 amino acids in the second EF-hand might play a key role for modulation of overall configuration of LC, thereby influencing the precise association of the key contacts.

Amino Acid Sequence↗
PubMed2001

Cost of nosocomial infection in Turkey: an estimate based on the university hospital data.

Nosocomial infections significantly affect the resource needs of hospitalized patients. They increase the mortality and morbidity of affected individuals and expose hospital staff to increased risk of infection. To estimate the additional resources needed in the hospital sector to deal with such infections, a sample of infection cases was selected from the Hacettepe University Hospital in Ankara, Turkey. Each case of nosocomial infection was matched with a noninfected case after controlling for age, sex, clinical diagnosis etc. of the patients. The empirical results indicate that hospital infection increases the average hospital stay by about four days. Total cost of an infected case, on average, was found to be $442 higher than that for a matched noninfected case. Using this incremental cost estimate, projections for Turkey implies that the hospital sector had to spend an additional $48 million in 1995 for medical management of nosocomial infections. The benefit: cost ratio for a hospital-based infection control programme is found to be about 4.6. Clearly, a programme for preventing nosocomial infections will not only pay for itself but also will generate other direct and indirect benefits to patients and society as a whole.

Cost Savings↗
PubMed2000

On the modulation of photoinduced fluorescence enhancement and conformational stability of albumin-bound bilirubin: effect of epsilon-NH(2) groups blocking and chloroform binding.

Photoinduced fluorescence enhancement of bilirubin bound to primary binding site on human serum albumin (HSA) was completely ceased when epsilon-NH(2) groups of its internal lysine residues were covalently blocked by acetylation or succinylation though the pigment bound to these derivatives in a folded conformation akin to that bound to HSA. These photoinduced fluorescence modulations cannot be ascribed to the binding of bilirubin to secondary low affinity sites as the CD spectrum of bilirubin bound to these derivatives showed complete inversion upon addition of chloroform which binds to subdomain IIA in HSA where high affinity bilirubin binding site is located. Presence of chloroform reconciled the photoinduced alterations in the CD spectrum observed in its absence, suggesting that chloroform stabilized the bound ligand against light but the fluorescence properties of bilirubin complexed with acetylated or succinylated derivatives remained unchanged. Guanidination of internal epsilon-NH(2) groups in HSA by O-methylisourea did not alter the spectral properties of the bound ligand. These results suggest that salt linkage(s) existing between epsilon-NH(2) groups of lysine residues in HSA and carboxyl groups of bilirubin, act(s) as a potential barrier during conformational rotation of the bound ligand assisted by photoactivation and their abolishment can alter its dynamics and stereoselectivity, a hitherto unnoticed implication of salt linkage(s) in BR-HSA complex.

Bilirubin↗
PubMed2000

Role of salt bridge(s) in the binding and photoconversion of bilirubin bound to high affinity site on human serum albumin.

The role of salt bridge(s) (between epsilon-NH(2) groups of lysine residues of human serum albumin (HSA) and carboxyl groups of bilirubin) in the binding and photoconversion of bilirubin bound to high affinity site on HSA was investigated by covalent modification of approximately 20% internal (buried) lysine residues of HSA with acetic anhydride, succinic anhydride and O-methylisourea and white light irradiation of their complexes with bilirubin. The different HSA derivatives, namely, acetylated HSA (aHSA), succinylated HSA (sHSA) and guanidinated HSA (gHSA), thus obtained, were found to be homogeneous with respect to charge and size and characterized in detail in terms of mean residue ellipticity, Stokes radius, tryptophan fluorescence, bilirubin binding and the photochemistry of their complexes with bilirubin. All the three derivatives retained helical contents and molecular size (Stokes radius) similar to HSA except for sHSA which showed a slight increase in the Stokes radius from 3.56 to 3.64 nm. Further, fluorescence properties of aHSA and sHSA were also found to be different from HSA and gHSA. Based on difference spectral change, fluorescence quenching and fluorescence enhancement results of bilirubin bound to HSA and its derivatives, nearly 46 and 48% reduction in bilirubin binding was observed in the case of aHSA and sHSA, respectively. Both aHSA and sHSA showed a decrease of 8- and 10-fold, respectively, in association constant compared to native HSA. Although the bisignate circular dichroism (CD) spectra of an equimolar (1:1) bilirubin-HSA complex was retained by all three HSA derivatives, the intensity of both positive and negative CD Cotton effects decreased significantly in both aHSA and sHSA. gHSA which retained net charge identical to native HSA, showed little decrease in bilirubin binding and the intensity of bisignate CD Cotton effects. The photochemical reaction of bilirubin bound to aHSA and sHSA produced opposite results to those observed with HSA and gHSA. A brief (2 min) irradiation of an equimolar complex of bilirubin with both aHSA and sHSA accompanied a rapid shift (14-15 nm) in the absorption spectrum of the bound pigment towards the blue region and almost complete elimination of negative CD Cotton effects while only moderately affecting the magnitude of positive CD Cotton effects. On the other hand, similar treatment of the complexes of bilirubin with HSA and gHSA did not show any change in the absorption spectrum, only a slight decrease in the intensity of both positive and negative CD Cotton effects was observed. The fluorescence intensity of bilirubin bound to HSA and gHSA was increased upon irradiation with white light and after 30 min it was nearly twice the value observed at 0 min irradiation. Interestingly, no change in the fluorescence intensity of bilirubin bound either to aHSA or sHSA was observed upon irradiation, even on increasing the duration of irradiation to 1 h. Taken together, the results on fluorescence quenching, fluorescence enhancement, CD spectral changes and visible absorption spectroscopy suggest that salt bridge(s) of the type (-COO(-).(+)H(3)N-) in which the epsilon-NH(2) group(s) contributed by lysine residues, are not only involved in the enantioselective binding of bilirubin but also in the stereospecific photoisomerization of bilirubin bound to a high affinity site on HSA.

Bilirubin↗
PubMed2000

Inhibition of heparin/protamine complex-induced complement activation by Compstatin in baboons.

Complement activation products are major components of the inflammatory response induced by cardiac surgery and cardiopulmonary bypass which contribute to postoperative organ dysfunction, fluid accumulation, and morbidity. Activation of the complement system occurs during extracorporeal circulation, during reperfusion of ischemic tissue, and after the formation of heparin-protamine complexes. In this study we examine the efficacy of Compstatin, a recently discovered peptide inhibitor of complement, in preventing heparin/protamine-induced complement activation in baboons. The study was performed in baboons because Compstatin binds to baboon C3 and is resistant to proteolytic cleavage in baboon blood (similar to humans); Compstatin inhibits only the activation of primates' complement system. After testing various doses and administration regimens, Compstatin produced complete inhibition at a total dose of 21 mg/kg when given as a combination of bolus injection and infusion. Compstatin completely inhibited in vivo heparin/protamine-induced complement activation without adverse effects on heart rate or systemic arterial, central venous, and pulmonary arterial pressures. This study indicates that Compstatin is a safe and effective complement inhibitor that has the potential to prevent complement activation during and after clinical cardiac surgery. Furthermore, Compstatin can serve as the prototype for designing an orally administrated drug.

Animals↗
PubMed2000

High-molecular-weight kininogen preadsorbed to glass surface markedly reduces neutrophil adhesion.

Adsorbed proteins on biomaterial surfaces determine whether cells adhere, but rheological variables are also critical. Neutrophil adhesion under well-defined radial flow conditions was studied on glass preadsorbed with plasma proteins or plasma protein domain fragments. Fibrinogen, low-molecular-weight kininogen (LK), high-molecular-weight kininogen (HK), cleaved HK (HKa), and recombinant HK domains 3 and 5 (D3 and D5H) were used. The number of adherent cells on the HK and HKa surfaces was less than 10% that found on the fibrinogen absorbed surface. The degree of spreading was minimal and detachment of adherent neutrophils was observed. HK and HKa contain binding sites for both anionic surfaces and neutrophils in the same domain (D5H). When adsorbed to surfaces, HK and HKa did not have the neutrophil binding sites available and therefore exhibited an anti-adhesive effect. Although D5H contains anionic surface binding sites, its small molecular size required a higher number of adsorbed molecules to cover the surface before a significant decrease in cell adhesion was observed. Since LK and D3 do not possess specific anionic surface binding sites, the adsorption of these proteins on glass was very low compared to HK and HKa. Thus, extensive cell adhesion and spreading were observed on the surfaces partially covered with preadsorbed LK and D3.

Adsorption↗
PubMed2000

Chloroform-induced conformational changes in the bound pigmentin bilirubin-albumin complexes.

Chloroform-induced conformational changes of bilirubin (BR) bound to different serum albumins were studied by circular dichroism (CD) and fluorescence spectroscopy. Addition of a small amount of chloroform ( approximately 20 mM) to a solution containing 20 microM albumin and 15 microM BR changed the sign order and magnitude of the characteristic CD spectra of all BR-albumin complexes except BR-PSA complex which showed abnormal behavior. Monosignate negative CD Cotton effects (CDCEs) of BR complexed with SSA, GSA and BuSA were transformed into bisignate CDCEs in presence of chloroform akin to those exhibited by chloroform free solution of BR-HSA complex, indicating that the pigment acquired right handed plus (P) chirality when chloroform was added to these complexes. Bisignate CD spectra of BR complexed with HSA and BSA showed complete inversion upon addition of chloroform corroborating earlier findings. On the other hand, changes observed with BR-RSA complex were slightly different showing an additional CD band of weak intensity centered around 390 nm though inversion of CDCEs was similar to that of BR-HSA complex. Monosignate CD spectra of BR-PSA complex also showed three CD bands occurring at 409, 470 and 514 nm after chloroform addition. These results indicated significant but different effects of chloroform on the conformation of bound BR in BR-albumin complexes which can be ascribed to the changes in the exciton chirality of bilirubin probably due to altered hydrophobic microenvironment induced by the binding of chloroform at or near the ligand binding site. Chloroform severely quenched the intrinsic tryptophan fluorescence of the protein and shifted the emission maxima towards blue region in all the albumins except PSA. However, quantitative differences in both quenching and blue shift were noted in different serum albumins. This suggests that chloroform probably binds in the close vicinity of tryptophan residue(s) located in subdomain(s) IIA or IB and II both. The fluorescence of BR-albumin complexes was also found to be sensitive to the presence of a small amount of chloroform. But the changes observed in the fluorescence of the bound pigment in presence of chloroform were less marked as compared to the changes in the intrinsic fluorescence of protein per se. Taken together, these results suggest that there is at least one conserved site for chloroform binding in all these albumins which is at or near the BR binding site.

Bilirubin↗
PubMed2000

The pattern of suicide in Pakistan.

There is paucity of information on suicide from Pakistan, an Islamic country in which data collection poses formidable challenges. A variety of social, legal, and religious factors make reporting and diagnosing suicide difficult. Paradoxically, incidents of suicide are regularly reported in newspapers in Pakistan. In the absence of other means these reports serve a useful, though basic information source for suicidal deaths. A 2-year analysis of all such reports in a major newspaper in Pakistan showed 306 suicides reported from 35 cities. Men (n = 208) outnumbered women by 2:1. While there were more single than married men, the trend was reversed in women. The majority of subjects were under 30 years of age and "domestic problems" was the most common reason stated. More than half the subjects used organophosphate insecticides, while psychotropics and analgesics were used infrequently. The study challenges the widely held belief that suicide is a rare phenomena in an Islamic country like Pakistan, and underscores the need for more culture specific research on this important public health problem.

Adolescent↗
PubMed2000

Use of nitric-oxide-eluting polymer-coated coronary stents for prevention of restenosis in pigs.

BACKGROUND: Restenosis after angioplasty remains an unresolved problem despite an increase in use of coronary stents. It has been theorized that nitric oxide (NO) exerts several actions that can prevent restenosis. These include inhibition of proliferation of smooth muscle cells, prevention of arterial spasms, and decreasing aggregation of platelets in response to exposure to collagen. OBJECTIVE: To determine whether NO coated stents decrease restenosis in a pig balloon injury model. METHODS: We used coronary stents impregnated with a slow-release precursor of NO in the porcine model of restenosis. Tantalum coil coronary stents (Cordis) were coated with a polymer impregnated with a slow-release precursor of NO. Polymer-coated stents without active precursors were used as controls. Oversized stents were mounted on a delivery balloon and subsequently deployed in the right coronary and left anterior descending arteries of each animal. RESULTS: Repeated recording of angiograms demonstrated that changes in minimum lumen diameter on going from immediately after stenting to 28-day follow-up for the control and NO-eluting-stent groups were similar, namely decreases of 1.89 +/- 0.33 and 2.08 +/- 0.28 mm, respectively. The morphometric results, showing that severe luminal narrowing occurred for both groups, were similar. The percentage area stenoses were 85 +/- 5% for the control group and 84 +/- 6% for the NO-eluting group. Histology demonstrated that profuse formation of neointima and an inflammatory cell infiltrate occurred. CONCLUSIONS: Severe diameter stenosis occurred both for control and for treatment groups. The degree of angiographic stenosis was markedly worse than that previously reported for this model. Sustained release of a precursor of NO did not prevent restenosis in this model. This might have been due to a lack of efficacy of nitric oxide or to a profuse and overwhelming stimulatory effect of the polymer in the coated stents.

Angioplasty, Balloon, Coronary↗
PubMed2000

Fast skeletal muscle isoforms exhibit the highest incorporation level into myofibrils and stress fibers among members of myosin alkali light chain isoform family.

Isoproteins of myosin alkali light chain (LC) were co-expressed in cultured chicken cardiomyocytes and fibroblasts and their incorporation levels into myofibrils and stress fibers were compared among members of the LC isoform family. In order to distinguish each isoform from the other, cDNAs of LC isoforms were tagged with different epitopes. Expressed LCs were detected with antibodies to the tags and their distribution was analyzed by confocal microscopy. In cardiomyocytes, the incorporation level of LC into myofibrils was shown to increase in the order from nonmuscle isoform (LC3nm), to slow skeletal muscle isoform (LC1sa), to slow skeletal/ventricular muscle isoform (LC1sb), and to fast skeletal muscle isoforms (LC1f and LC3f). Thus, the hierarchal order of the LC affinity for the cardiac myosin heavy chain (MHC) is identical to that obtained in the rat (Komiyama et al., 1996. J. Cell Sci., 109: 2089-2099), suggesting that this order may be common for taxonomic animal classes. In fibroblasts, the affinity of LC for the nonmuscle MHC in stress fibers was found to increase in the order from LC3nm, to LC1sb, to LC1sa, and to LC1f and LC3f. This order for the nonmuscle MHC is partly different from that for the cardiac MHC. This indicates that the order of the affinity of LC isoproteins for MHC varies depending on the MHC isoform. Further, for both the cardiac and nonmuscle MHCs, the fast skeletal muscle LCs exhibited the highest affinity. This suggests that the fast skeletal muscle LCs may be evolved isoforms possessing the ability to associate tightly with a variety of MHC isoforms.

Animals↗
PubMed2000

The prevalence and types of coronary artery anomalies in Northern Ireland.

Coronary artery anomalies are uncommon, with a reported prevalence ranging from 0.2% to 1.6%. It is important that those who undertake coronary angiographic procedures are aware of the spectrum of these anomalies. Interventional percutaneous coronary revascularisation procedures are widely used in the management of patients with symptomatic coronary atherosclerosis. The presence of a coronary artery anomaly may make these procedures technically challenging. We have reviewed the Cardiac catheterisation database at the Royal Victoria Hospital, Belfast, and report the prevalence and types of these anomalies.

Adult↗
PubMed2000

Sequence diversity of a fragment of the 16S RNA gene from Helicobacter pylori.

Helicobacter pylori is one of the most common bacterial pathogens. It is the main cause of gastric and duodenal ulcers and has been associated with other diseases. The organism seems to be more genetically diverse than other bacterial pathogens, and the source of these differences awaits explanation. The sequence of a fragment of the 16S rRNA gene was determined for ten strains of H. pylori to examine the contribution of point mutation within a conserved gene. There were few differences between the sequences from the various strains and it was concluded that such differences were not the most important source of diversity.

Base Sequence↗